Foxp2 regulation of sex specific transcriptional pathways and brain development

描述(由申请人提供)：发生精神疾病或神经障碍的相对风险因性别而有很大差异。男性自闭症和自闭症谱系障碍(ASD)、多发性抽动症、口吃、阅读障碍和早发性精神分裂症的发病率要高得多，所有这些都是儿童期发病的。相比之下，女性患抑郁症、焦虑症、厌食症、暴食症和精神分裂症晚发的几率要高得多，所有这些都有成人发病。这些性别偏见的生物学基础是完全未知的。通过使用哺乳动物动物模型探索男性和女性大脑发育的不同，我们可以洞察疾病性别差异的潜在来源，并确定潜在的治疗和预防目标。此外，FOXP2基因已知在大脑的几个区域表达，这些区域与动物的语音交流和人类的语言有关。FOXP2对下游信号通路的调控为其在ASD中发挥作用提供了强有力的支持。解释人类语言中性别差异的机制也是未知的，尽管性激素，主要是雄激素，已知在包括灵长类在内的各种动物物种的发声发展中发挥核心作用。尽管迄今为止，自闭症相关基因、语言或性激素之间的关系尚未确定，但也有人假设，在产前发育过程中，暴露在雄激素水平增加的环境中是ASD病因的基础。该方案的第一个目标是研究FOXP2表达的性别差异如何影响性别特异性神经回路的发展，以及该回路如何对性别特异性行为(例如，语音交流和社会互动)负责。实验1.1和1.2旨在填补我们知识的第一个空白，探索在新生儿发育期抑制Foxp2对男性和女性发声和社会行为的不同影响。如上所述，以前研究ASD和FOXP2的工作没有考虑性别差异和激素对FOXP2调控的转录信号通路的潜在影响。因此，这项建议的第二个目标是确定性激素如何介导Foxp2‘S对基因表达的调控。实验2.1和2.2旨在通过评估性激素对Foxp2转录信号通路的影响来解决这个问题。从以前的研究中已经知道，Foxp2影响负责高级认知功能的大脑区域的发育。然而，到目前为止，我们还不知道这种发育在多大程度上与男性和女性的大脑发育相似或不同。这项建议的第三个目标是确定性激素和Foxp2的相互作用在多大程度上改变了性别特异性神经元的发育。实验3.1和3.2旨在通过量化在存在和不存在针对Foxp2的慢病毒敲除的情况下性激素对Foxp2蛋白水平的影响来解决这个问题。对于R00阶段，我将撰写从AIMS 1.2和AIMS 2.1和2.1收集的研究。然后，我将开始设置我的实验室。在开放实验室的同时，我将开始AIM的工作 3.

DESCRIPTION (provided by applicant): The relative risk of developing a mental illness or neurological disorder varies considerably by gender. Males exhibit far higher rates of autism and autism spectrum disorder (ASD), Tourette's Syndrome, stuttering, dyslexia, and early onset of schizophrenia, all of which have a childhood onset. In contrast, females suffer much higher incidences of major depressive disorders, general anxiety disorder, anorexia, bulimia, and late onset of schizophrenia, all of which have adult onsets. The biological basis for these gender biases is entirely unknown. By exploring how the brain develops differently in males and females, using a mammalian animal model, we can gain insight into the potential sources of the sex differences in disease and identify potential therapeutic and preventive targets. Moreover, the gene FOXP2 is known to be expressed in several areas of the brain involved in vocal communication in animals and language in humans. There is strong support for FOXP2 playing a role in ASD can be found in its regulation of downstream signaling pathways. The mechanism that explains the basis for the gender difference in human language is also unknown, although, sex hormones, principally androgens, are known to play a central role in the development of vocalizations in a wide variety of animal species including primates. It has also been hypothesized that exposure to increased levels of androgens, during prenatal development, underpin the etiology of ASD, although to date, no relationship between any autism associated gene, language, or sex hormones has been established. The first goal of this proposal is to investigate how sex differences in Foxp2 expression influence the development of sex specific neural circuitry and how this circuitry is accountable for sex specific behaviors (e.g., vocal communication and social interactions). Experiments 1.1 and 1.2 are designed to fill the first gap in our knowledge, by exploring how suppression of Foxp2 during the neonatal developmental period impacts both vocalization and social behavior differently in males versus females. As discussed above, previous work investigating ASD and FOXP2, has not taken the perspective of the potential impact sex differences and hormones have on transcriptional signaling pathways regulated by FOXP2. Thus, A second goal of this proposal is to determine how sex hormones mediate Foxp2's regulation of gene expression. Experiments 2.1 and 2.2 are designed to address this question by assessing what are the effects sex hormones have on Foxp2 transcriptional signaling pathways. From previous research, it is known that Foxp2 influences the development of brain regions responsible for higher cognitive functioning. However, to date it is not known to what extent this development is similar or different with regards to male and female brain development. The third goal of this proposal is to ascertain the extent to which the interaction of sex hormones and Foxp2 alters sex specific neuronal development. Experiments 3.1 and 3.2 are designed to address this question by quantifying the impact sex hormones have on Foxp2 protein levels both in the presence and absence of lentiviral knockdown targeting Foxp2. For the R00 phase, I will write up the research collected from Aims 1.2 and Aims 2.1 and 2.1. I will then begin setting up my lab. Concurrent with opening the lab, I will begin work on Aim 3.